Stopping sepsis

Sepsis is a dreaded diagnosis; clinicians have few tools to fight this generalized inflammatory response to infection that too often results in death. A new nanoparticle described by Spence et al. may prove to be a welcome weapon in the antisepsis arsenal. The nanoparticles are coated with di(α2→8) N-acetylneuraminic acid (NANA), which mimics sialic acid, the natural ligand for a critical anti-inflammatory receptor found on macrophages. This so-called Siglec receptor (sialic acid–binding immunoglobulin-like lectin-E) down-regulates macrophage activation by inflammatory signals released during infection and tissue damage, thereby interrupting the chain of events leading to sepsis. The authors demonstrate that the nanoparticle boosts this anti-inflammatory response in culture, and also show that it improves survival in two mouse models of generalized sepsis and one of pulmonary injury. Most encouraging for the ultimate utility of this nanoparticle in human patients, the nanoparticle is effective in human macrophages and in a sophisticated ex vivo model of human lung edema.

Abstract

Sepsis is the most frequent cause of death in hospitalized patients, and severe sepsis is a leading contributory factor to acute respiratory distress syndrome (ARDS). At present, there is no effective treatment for these conditions, and care is primarily supportive. Murine sialic acid–binding immunoglobulin-like lectin-E (Siglec-E) and its human orthologs Siglec-7 and Siglec-9 are immunomodulatory receptors found predominantly on hematopoietic cells. These receptors are important negative regulators of acute inflammatory responses and are potential targets for the treatment of sepsis and ARDS. We describe a Siglec-targeting platform consisting of poly(lactic-co-glycolic acid) nanoparticles decorated with a natural Siglec ligand, di(α2→8) N-acetylneuraminic acid (α2,8 NANA-NP). This nanoparticle induced enhanced oligomerization of the murine Siglec-E receptor on the surface of macrophages, unlike the free α2,8 NANA ligand. Furthermore, treatment of murine macrophages with these nanoparticles blocked the production of lipopolysaccharide-induced inflammatory cytokines in a Siglec-E–dependent manner. The nanoparticles were also therapeutically beneficial in vivo in both systemic and pulmonary murine models replicating inflammatory features of sepsis and ARDS. Moreover, we confirmed the anti-inflammatory effect of these nanoparticles on human monocytes and macrophages in vitro and in a human ex vivo lung perfusion (EVLP) model of lung injury. We also established that interleukin-10 (IL-10) induced Siglec-E expression and α2,8 NANA-NP further augmented the expression of IL-10. Indeed, the effectiveness of the nanoparticle depended on IL-10. Collectively, these results demonstrated a therapeutic effect of targeting Siglec receptors with a nanoparticle-based platform under inflammatory conditions.